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DIURETIC DRUGSDIURETIC DRUGS

Introduction Introduction

Are drugs that induce a state of Are drugs that induce a state of increased urine flow. increased urine flow.

Are inhibitors of renal ion Are inhibitors of renal ion transporters that decrease the transporters that decrease the reabsorption of Nareabsorption of Na⁺ at different sites in ⁺ at different sites in the nephron such that Na⁺ and other ions the nephron such that Na⁺ and other ions enter the urine in greater than normal enter the urine in greater than normal amounts along with water.amounts along with water.

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Uses of diureticsUses of diuretics

Disorders involving abnormal fluid Disorders involving abnormal fluid retention (edema)retention (edema)

Treatment of hypertensionTreatment of hypertension

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Diuretic classesDiuretic classes

DRUGSDRUGS

Carbonic anhydrase Carbonic anhydrase inhibitorsinhibitors

Loop diureticsLoop diuretics Thiazide diureticsThiazide diuretics Potassium sparing Potassium sparing

diureticsdiuretics Osmotic diureticsOsmotic diuretics

SITE OF ACTIONSITE OF ACTION

PCTPCT

Ascending LHAscending LH DCTDCT Collecting tubulesCollecting tubules

All areas in the All areas in the nephronnephron

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Diuretics:Diuretics:Sites of ActionSites of Action

Na+

Cl-

K+

Na+

Cl-HCO3

-

Na+

K+

Carbonic Anhydrase Inhibitors

Eg: Acetazolamide

Loop DiureticsEg: Furosemide

ThiazidesEg: Chlorothiazide

K+ - SparingEg: spinolactone

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CARBONIC ANHYDRASE CARBONIC ANHYDRASE INHIBITORSINHIBITORS

AcetazolamideAcetazolamide DorzolamideDorzolamide MethazolamideMethazolamide

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CARBONIC ANHYDRASE CARBONIC ANHYDRASE INHIBITORSINHIBITORS

ACTION : INHIBITS CARBONIC ACTION : INHIBITS CARBONIC ANHYDRASE ENZYMEANHYDRASE ENZYME

SITESITE : PCT : PCT EFFECTS EFFECTS : NO H+ FOR : NO H+ FOR

REABSORPTION OF Na +REABSORPTION OF Na +– HCO3- EXCRETION INCREASESHCO3- EXCRETION INCREASES– CAUSES MILD DIURESISCAUSES MILD DIURESIS– ↓↓NaNa⁺/H⁺ antiport⁺/H⁺ antiport– ↑↑Cl⁻ in the blood---hyperchloremiaCl⁻ in the blood---hyperchloremia

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Causes significant bicarbonate Causes significant bicarbonate loss causing loss causing alkalinization of alkalinization of urineurine

Hyperchloremic metabolic Hyperchloremic metabolic acidosis acidosis

reduction in aqueous humor reduction in aqueous humor production production

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THERAPEUTIC USESTHERAPEUTIC USES

Chronic treatment of GLAUCOMA Chronic treatment of GLAUCOMA ( MC INDICATION )( MC INDICATION )– REDUCES AQUEOUS HUMOR REDUCES AQUEOUS HUMOR

PRODUCTIONPRODUCTION– DECREASES IOP.DECREASES IOP.

DRUGS USED : ACETAZOLAMIDE, DRUGS USED : ACETAZOLAMIDE,

DORZOLAMIDE.DORZOLAMIDE.

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Acute Mountain SicknessAcute Mountain Sickness

Given nightly for 5 days before the Given nightly for 5 days before the ascent to prevent ascent to prevent weakness, weakness, breathlessness, dizziness, nausea, breathlessness, dizziness, nausea, cerebral and pulmonary edemacerebral and pulmonary edema

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OTHER USESOTHER USES

-- Metabolic alkalosis-- Metabolic alkalosis

Can decrease production of CSF, Can decrease production of CSF, therefore used to treat pseudotumor therefore used to treat pseudotumor cerebricerebri

SIDE EFFECTSSIDE EFFECTS

BICARBONATURIABICARBONATURIA HYPOKALEMIAHYPOKALEMIA HYPERCHLOREMIAHYPERCHLOREMIA PARESTHESIASPARESTHESIAS RENAL STONES (calcium oxalate, struvite RENAL STONES (calcium oxalate, struvite

stone)stone) SULFONAMIDE HYPERSENSITIVITYSULFONAMIDE HYPERSENSITIVITY CI: in hepatic cirrhosis(hepatic CI: in hepatic cirrhosis(hepatic

encephalopathy)encephalopathy)1414

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Loop Diuretic DrugsLoop Diuretic Drugs

Furosemide Furosemide BumetanideBumetanide Torsemide Torsemide

Ethacrynic acid --no longer in use Ethacrynic acid --no longer in use because of toxicity. because of toxicity.

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ActionAction Inhibit the Inhibit the Na/K/Cl transport system Na/K/Cl transport system in in

the luminal membrane of the thick the luminal membrane of the thick ascending limb of Henle.ascending limb of Henle.

Reabsorption of Na/K/Cl reduced Reabsorption of Na/K/Cl reduced → their → their excretionexcretion..

Increases Ca²Increases Ca²⁺, mg²⁺⁺, mg²⁺ excretion excretion

The most efficacious of all the diureticsThe most efficacious of all the diuretics They increase the synthesis of They increase the synthesis of

prostaglandins, with their diuretic effect prostaglandins, with their diuretic effect enhanced by prostaglandinsenhanced by prostaglandins

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USESUSES

Major uses: Major uses: --Edematous conditions--Edematous conditions Acute pulmonary edema Acute pulmonary edema Acute hypercalcemia Acute hypercalcemia Management of edema Management of edema HTN by HTN by ↓ing peripheral vascular resistance ↓ing peripheral vascular resistance

& reduction in blood volume& reduction in blood volume HyperkalemiaHyperkalemia Renal failureRenal failure

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SESE Ototoxicity: more with ethacrynic acidOtotoxicity: more with ethacrynic acid HypokalemiaHypokalemia Metabolic alkalosisMetabolic alkalosis HyperuricemiaHyperuricemia HypocalcemiaHypocalcemia hypomagnesemiahypomagnesemia GoutGout DehydrationDehydration Cardiac arrhythmias Cardiac arrhythmias Sulfonamide hypersensitivity except Sulfonamide hypersensitivity except

ethacrynic acidethacrynic acid

Drug interactionsDrug interactions

Aminoglycosides: Aminoglycosides: ↑ ototoxicity↑ ototoxicity ↑ ↑ Digoxin toxicity due to electrolyte Digoxin toxicity due to electrolyte

disturbance (hypokalemia)disturbance (hypokalemia) Chronic administration ↓es lithium Chronic administration ↓es lithium

clearanceclearance

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THIAZIDESTHIAZIDES

Most commonly used diuretic.Most commonly used diuretic. Inhibition of NaInhibition of Na⁺⁺/Cl/Cl⁻⁻ transporter from transporter from

the distal convoluted tubule.the distal convoluted tubule. ↑↑ing Naing Na⁺⁺ and Cl and Cl⁻ excretion ⁻ excretion → to ↑ diuresis→ to ↑ diuresis Enhance calcium reabsorption in the Enhance calcium reabsorption in the

distal convoluted tubule – reduces Ca distal convoluted tubule – reduces Ca excretion.excretion.

Loss of K Loss of K

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Drugs Drugs

ChlorothiazideChlorothiazide ChlorthalidoneChlorthalidone HydrochlorothiazideHydrochlorothiazide IndapamideIndapamide MetalazoneMetalazone MethyclothiazideMethyclothiazide TrichlomethiazideTrichlomethiazide

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USESUSES

Essential HTN by vasodilatation of Essential HTN by vasodilatation of peripheral vasculature (Kperipheral vasculature (K⁺ channel ⁺ channel opener)opener)

CHFCHF Renal failureRenal failure Nephrogenic Diabetes InsipidusNephrogenic Diabetes Insipidus HypercalciuriaHypercalciuria

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SESE HypokalemiaHypokalemia Metabolic alkalosisMetabolic alkalosis HyperuricemiaHyperuricemia HypercalcemiaHypercalcemia Cardiac arrhythmiasCardiac arrhythmias HypotensionHypotension HyponatremiaHyponatremia HyperlipidemiaHyperlipidemia Hypersensitivity to sulfonamidesHypersensitivity to sulfonamides Hyperglycemia Hyperglycemia

Drug interactionsDrug interactions

Increases digoxin toxicityIncreases digoxin toxicity Contraindicated in diabetics Contraindicated in diabetics

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POTASSIUM SPARING POTASSIUM SPARING DIURETICSDIURETICS

These diuretics inhibit aldosterone These diuretics inhibit aldosterone receptor at the Collecting tubule and receptor at the Collecting tubule and late distal tubule late distal tubule by stimulating Naby stimulating Na⁺⁺ excretion and Kexcretion and K⁺⁺ retention retention

ALDOSTERONE: ALDOSTERONE: It increases the reabsorption of It increases the reabsorption of

sodium and water.sodium and water. Excretion of potassium in the Excretion of potassium in the

distal tubules of the kidneys.distal tubules of the kidneys. Thus increases blood pressure. Thus increases blood pressure.

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Drugs Drugs

SpironolactoneSpironolactone

AmilorideAmiloride

TriamtereneTriamterene

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Drugs Drugs

SpironolactoneSpironolactone: inhibits aldosterone : inhibits aldosterone at its receptor sites.at its receptor sites.

Increasing Na and H2O excretion Increasing Na and H2O excretion while retaining Kwhile retaining K

USES OF SPIRONOLACTONEUSES OF SPIRONOLACTONE

Diuretic: Diuretic: given in conjunction with a given in conjunction with a thiazide and loop diuretics to prevent thiazide and loop diuretics to prevent K-excretionK-excretion

Diuretic of choice in patients with Diuretic of choice in patients with hepatic cirrhosishepatic cirrhosis

Secondary hyperaldosteronismSecondary hyperaldosteronism Heart failure to prevent cardiac Heart failure to prevent cardiac

remodelingremodeling

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SESE

Hyperkalemia Hyperkalemia Gynecomastia (spironolactone)Gynecomastia (spironolactone) Anti androgen effects Anti androgen effects

(spironolactone)(spironolactone) Menstrual irregularitiesMenstrual irregularities GIT disturbanceGIT disturbance

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Triamterene and AmilorideTriamterene and Amiloride

MOA: MOA: blocks Na transport channels blocks Na transport channels resulting in a decrease in Na/K resulting in a decrease in Na/K exchange not dependent on the exchange not dependent on the presence of aldosteronepresence of aldosterone

Causes retention of KCauses retention of K⁺⁺

Side effectSide effect

Leg cramps (Triamterene & Leg cramps (Triamterene & Amiloride) Amiloride)

Increased BUN (Triamterene & Increased BUN (Triamterene & Amiloride) Amiloride)

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Osmotic diureticsOsmotic diuretics

Have ability to carry water with them Have ability to carry water with them into the tubular fluid, therefore into the tubular fluid, therefore increasing water excretion.increasing water excretion.

Acts on all parts of the nephron.Acts on all parts of the nephron.

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OSMOTIC DIURETICSOSMOTIC DIURETICS

MANNITOL/ureaMANNITOL/urea Parental (I.V.)Parental (I.V.) increase water excretion.increase water excretion. Increased tubular fluid osmolarityIncreased tubular fluid osmolarity Increase urine volume.Increase urine volume. Less effect or no effect on Na excretionLess effect or no effect on Na excretion

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USESUSES

To increase urine volume in anuric To increase urine volume in anuric conditionsconditions

such as toxic ingestion, trauma, drug such as toxic ingestion, trauma, drug toxicities.toxicities.

To decrease intracranial or To decrease intracranial or intraocular pressure.intraocular pressure.

Acute renal failureAcute renal failure

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SESE

DehydrationDehydration Hypovolemia Hypovolemia HyponatremiaHyponatremia HeadacheHeadache Nausea & vomitingNausea & vomiting Pulmonary edema: very common Pulmonary edema: very common

with mannitolwith mannitol